One of the most promising engineering contributions to medicine is the development of nanoscale drug capsules that are invisible to healthy tissue while specifically directed to attack a diseased site. In the last 10 years, nanomedicine has experienced a surge of new opportunities expanding therapy to undrugable proteins with the discovery that small exogenous RNA bits delivered to the cytoplasm are able to deploy the shutdown of specific genes. We are now able to make short (19-21 bp) RNA sequences that can in principle turn off any given gene but none of this technology is useful until an efficient delivery vehicle is identified. RNAi therapy is currently experiencing a revival due to remarkable improvements in efficacy and viability through oligonucleotide chemical manipulations and/or via their packaging into nano-scale carriers but at present there is no FDA approved system for the application in humans. The design of the next generation of siRNA carriers requires a deep understanding of how nanoparticle's physicochemical properties truly impart biological stability and efficiency. For example, we now know that nanoparticles need to be sterically stabilized in order to meet adequate biodistribution profiles. However, the central hurdle in siRNA carrier design remains at the cellular level. Typically, an RNA-carrying particle will penetrate the cell via endocytosis and rest trapped until decomposition. In this work we will highlight the fact that the disruption of endosomes encompasses membrane transformations (for example pore formation) that cost significant elastic energy. In addition to surface chemistry, nanoparticle size and shape have been identified as relevant parameters controlling cellular uptake. In this work we propose that nanoparticle structural interiors are a novel handle to regulate endosomal escape. Lipid nanoparticles (LNP) have been long recognized as promising siRNA delivery vectors however virtually all studies are locked to the concept of using liposome formulations. In this work we will instill a new direction of LNP design where nanoparticle interiors comprise highly ordered networks of membranes with high surface-to-volume ratios and intrinsic membrane properties prone to disrupt endosomal membranes at minimal energetic cost. We will employ careful structural characterization of the nanoparticles combined with quantitative functional studies of siRNA delivery and gene knockdown to a variety of cell lines, including neurons and stem cells that are known to be hard to transfect. It is our goal to underpin the correlation between nanoparticle internal structures with the dynamic process of siRNA cellular delivery and enable the next generation of highly efficient RNAi nanomedicine.